Abstract CT171: A first-in-human phase I study of the ATM inhibitor M4076 in patients with advanced solid tumors (DDRiver Solid Tumors 410): Part 1A results
Authors: Lillian L. Siu, Timothy A. Yap, Sofia Genta, Gregory Pennock, Christine Hicking, Xiaoli You, Jatinder K. Mukker, Giuseppe Locatelli, Anthony W. Tolcher
Journal: Cancer Research (2023)

Abstract M4076 is a potent and selective oral inhibitor of ataxia-telangiectasia mutated (ATM), a key kinase of the DNA damage response (DDR) involved in double-strand break repair. Preclinically, M4076 when combined with DNA damage-inducing therapy or other DDR inhibitors caused unrestricted cell cycle progression and DNA damage accumulation, resulting in tumor cell death. Part 1A of this ongoing open-label study (NCT04882917) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and maximum tolerated dose (MTD) of M4076 monotherapy in patients (pts) with advanced solid tumors. Dose escalation was guided by safety, along with Bayesian analysis, PK, and PD. In total, 22 pts received M4076 at 4 different dose levels (100-400 mg once daily [QD]); 21 pts (95.5%) discontinued treatment (progressive disease: 11 [50%], adverse events [AEs]: 5 [22.7%]). Dose-limiting toxicities (DLTs) were reported in 4 pts. Overall, 6 pts had ≥1 treatment-related AE (TRAE) of Grade ≥3 (including one Grade 4 hypersensitivity). The most common TRAEs were rash and anemia (Table 1). MTD was determined at 300 mg QD. As per preliminary PK across cohorts, M4076 was rapidly absorbed with median Tmax ~0.5-2 h and mean elimination half-life (t1/2) ~2-10 h; exposure increased in a dose-related manner, with minimum accumulation after multiple QD doses. At ≥200 mg QD, unbound steady state plasma concentration exceeded in vivo pCHK2 IC90 throughout the dosing interval. PD evaluation was based on the modulation of γ-H2AX (a direct ATM target) in ex vivo bleomycin stimulated CD45+ lymphocytes, by flow cytometry. Preliminary analyses showed a trend of reduction of γ-H2AX levels from day 1 to day 2, reaching 80-100% of target inhibition on day 2 with the dose range 100-400 mg QD. The MTD of M4076 was determined, and target exposure and engagement were achieved without significant hematological toxicity. Future investigations on M4076 as combination therapy are planned. Table 1. Safety overview Dose (Safety set) Patients with TRAEs (Grade ≥3) DLT analysis set (Patients with ≥80% of the planned dose or DLT per investigator) DLT DLT AE terms 100 mg(n = 2) No n = 2 No NA 200 mg(n = 7) n = 1 (decreased lymphocyte count, maculo-papular rash) n = 5 Yes(n = 1) Grade 3 maculo-papular rash (TRAE, required drug withdrawal; resolved) 300 mg(n = 9) n = 3 (anemia, spontaneous bacterial peritonitis) n = 7 Yes(n = 1) Grade 1 maculo-papular rash; Grade 2 fever (TRAEs, required treatment discontinuation; resolved) 400 mg(n = 4) n = 2 (nausea, maculo-papular rash, hypersensitivity) n = 4 Yes(n = 2) Grade 3 maculo-papular rash (TRAEs, required dose reduction/interruption and/or concomitant medication; resolved) MedDRA version 23.0, NCI-CTCAE version 5.0. Data cutoff: 2 Nov 2022 AE, adverse event; DLT, dose-limiting toxicity; NA, not applicable; TRAE, treatment-related AE Citation Format: Lillian L. Siu, Timothy A. Yap, Sofia Genta, Gregory Pennock, Christine Hicking, Xiaoli You, Jatinder K. Mukker, Giuseppe Locatelli, Anthony W. Tolcher. A first-in-human phase I study of the ATM inhibitor M4076 in patients with advanced solid tumors (DDRiver Solid Tumors 410): Part 1A results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT171.